Hormone therapy is making a comeback

Menopausal women searching for relief of hot flushes don’t have to forgo estrogen, say experts. The hormone might even prevent CHD and diabetes.

When do the benefits of hormone therapy for menopausal women outweigh the risks? An updated position statement from the North American Menopause Society (NAMS) suggests that estrogen therapy (ET) or the combination of estrogen and progesterone therapy (EPT) offers the greatest benefit and smallest risk to women who are within 10 years of menopause. ET is recommended for women who have had hysterectomies. EPT is needed by other women to reduce the risk of endometrial cancer that ET alone causes.

Like its 2004 position statement, the 2007 NAMS update supports the short-term use of hormone therapy (HT) for hot flushes, night sweats, and other menopausal symptoms (www.menopause.org/PSHT07.pdf. Accessed April 1, 2007). However, the statement puts into new perspective the increased risk of heart attacks that caused the federal government to halt the Women’s Health Initiative (WHI), a planned 15-year study of the effects of HT on the risks of cardiovascular disease (CVD), osteoporosis, and cancer among postmenopausal women.

For the first time, NAMS acknowledged that HT reduces the risk of diabetes—an important and often overlooked finding that emerged from the WHI and other studies. The NAMS panel also weighed the pros and cons of lower-than-standard doses of HT, patches vs. pills, and the advisability of long-term therapy for women with severe menopausal symptoms that just won’t quit.

Age is key

The updated position statement emphasizes how the benefits and risks of HT differ with age. It also provides reassuring data on the incidence of heart attacks among newly menopausal women who may need short-term HT for relief of symptoms. “The original fear factor generated by first announcements of the WHI was exaggerated,” says Wulf Utian, MD, PhD, executive director of NAMS and chair of the advisory panel that developed the new position statement. “There’s now a far greater understanding of the WHI data,” as well as the escalating amount of research published since then.

NAMS describes its position statements as “prevailing opinion pieces” aimed at incorporating current evidence into clinical recommendations, not “practice standards” to be used by regulating bodies and insurance companies.

In the 2007 statement, the panel focused on the differences in risks between women in the early stages of menopause—the years immediately after a woman’s last menstrual period
—and women who are 10 or more years past menopause. “There is a real philosophical difference between initiation of hormone therapy for symptom relief during perimenopause and initiation of systemic hormone therapy five, 10, or more years beyond menopause” for indications unrelated to symptoms, the panel stated.

For example, experts noted that coronary heart disease (CHD) risks were “considerably lower in younger, newly postmenopausal women” than among those 10 years or more past menopause. On average, the women who were enrolled in the WHI began HT more than a decade after menopause. For these women, risk of heart disease rose by 22% in the 10-19 years after menopause and by 71% in the 20 or more years after menopause.

The more recent findings suggest that for younger women, HT used to treat menopausal symptoms does not present the risk of CHD seen in the WHI. Instead, the panel noted that the risk of CHD among these women attributable to HT is very low and that, in fact, HT may be protective. While there is insufficient evidence to say that the reduced risk (11% lower than women of the same age who were not on HT) is adequate reason to put younger women on HT, Dr. Utian says that fear of CHD is unjustified.

Benefits and hazards

The panel reached the following conclusions on other risks:

• Venous thromboembolism (VTE): Both observational studies and randomized controlled trials have found an increased risk of VTE among postmenopausal women on ET or EPT. The risk appears during the first year or two after starting therapy and then decreases over time. In the WHI, VTE risk associated with EPT among women aged 50-59 was 11 additional cases per 10,000 women per year and, with ET, two additional cases per 10,000 women per year. The panel suggests that lower doses of oral estrogens may present less of a VTE risk than higher doses.

• Stroke: Both ET and EPT appear to increase the risk of ischemic stroke in postmenopausal women, but the absolute risk is lower among women aged 50-59 than in older women. Although HT may not significantly influence the risk of stroke among women with a history of CHD or ischemic cerebrovascular disease, those with prevalent CVD do have a high baseline risk of stroke, and HT should be “particularly avoided.”

• Diabetes mellitus: On the positive side, the NAMS experts noted that large randomized controlled trials, including the WHI, have suggested that HT reduces the incidence of diabetes among postmenopausal women. “When bad news comes out of WHI, it gets significant publicity, but good
news is ignored,” complained Dr. Utian of this previously unheralded finding. In the WHI, women on EPT had a 21% reduced risk of diabetes, while women on ET had a 12% lower risk. The reason for this benefit is unknown. It may be due to lower weight gain or reduced insulin resistance among these women. Despite the documented lower risks, there is inadequate evidence to recommend HT solely for diabetes prevention in perimenopausal women.

• Breast cancer: One of the reasons the WHI was halted was that it showed an increased risk of breast cancer with more than five years of EPT use, although no increased risk was seen among women on ET for an average of 7.1 years (the panel did cite limited observational data, suggesting that ET for more than 15 years may increase breast cancer risk). The statement also noted that EPT and, to a lesser extent, ET increase breast-cell proliferation, breast pain, and mammographic density and that HT may impede the diagnostic interpretation of mammograms.

• Osteoporosis: Although evidence demonstrates that both ET and EPT reduce the risk of postmenopausal fractures due to osteoporosis, HT should be considered for prevention only after weighing its benefits and risks against those of other products. However, protection against fractures was one of only two reasons the panel found to support long-term, lowest-effective dose HT. Long-term treatment is acceptable for two groups: (1) those at high risk of fractures who also have moderate-to-severe menopausal symptoms and (2) those with established reduction in bone mass for whom alternate therapies are not appropriate or cause side effects, or when the outcome of extended alternate therapies are unknown.

• Depression: Evidence that the risk of depression is higher in early postmenopause is mixed. Two small randomly controlled trials have found that short-term ET is effective for the treatment of affected perimenopausal women, while another trial found no such benefit for depressed older postmenopausal women. The panel found insufficient evidence for using HT to treat depression in general.

• Dementia and cognitive decline: No evidence was found to support the use of HT to prevent dementia or cognitive decline. The panel warned that starting EPT after age 65 for these reasons may actually increase risk of dementia within the subsequent five years. Studies of whether dementia can be prevented in women who begin HT during the menopause transition or early postmenopause offered insufficient evidence of help or harm. ET does not appear to have any effect on Alzheimer’s disease.

• Premature menopause and premature ovarian failure: These conditions are associated with a lower-than-normal risk of breast cancer but an earlier onset of osteoporosis and CHD. The effects of ET or EPT remain an open question. The risk-benefit ratio for women who begin therapy at an early age may be more favorable but is currently unknown.

How low can you go?

In recent years, clinicians have been prescribing lower doses of ET and EPT than the 0.625 mg/day of conjugated equine estrogens used in the WHI. “Escalating evidence suggests that as you reduce the dose, you potentially reduce the level of risk, but we have no long-term studies to absolutely prove that,” said Dr. Utian. However, many studies have shown that lower doses preserve bone mineral density and offer relief from hot flushes, night sweats, and vaginal dryness and atrophy that is nearly equivalent to the standard dose used in the WHI.

Lower doses include 0.3 mg oral conjugated estrogens daily, 0.25-0.5 mg oral micronized 17ß-estradiol, 0.025 mg transdermal 17ß-estradiol patch, or the equivalent. A very low-dose 14 µg/day transdermal 17ß-estradiol patch for osteoporosis prevention is available in the United States, but its long-term impact on the incidence of fractures is unknown.

In considering the duration of use, the position statement includes only one exception other than protection against osteoporotic fractures—when a woman who is fully informed of the benefits and risks judges that symptom relief outweighs the risks after trying but failing to stop HT.

The panel failed to reach a consensus on the best way to discontinue HT (see “Discontinuing hormone therapy”) and whether the effects of continuous-combined EPT are different from continuous-sequential EPT. Evidence indicates that continuous progestogen (in the doses administered in the WHI) may be related to increased risk of CHD and breast cancer, but data are conflicting and the panel offered no recommendation.
The question surrounding the pros and cons of administering ET/EPT in patches rather than pills remains open. On the plus side, some evidence suggests transdermal 17ß-estradiol may present a lower risk of deep venous thrombosis than estrogen in pill form. But no advantage was seen for patches over pills when it comes to breast cancer (the panel cited results of a large observational study, which showed that both similarly increase the risk).

The panel urged caution in extrapolating data from the WHI and the Heart and Estrogen/Progestin Replacement Study, which looked at the effect of EPT on women with heart disease. No trials have established how long-term use of HT affects the risks of breast cancer, CHD, stroke, and fractures among symptomatic postmenopausal women younger than 50.

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